Despite numerous clinical trials over the past several decades, the prognosis for pediatric patients with diffuse intrinsic pontine glioma (DIPG) remains grim. Currently, there is only one validated treatment for improving median survival of patients with DIPG: fractionated radiation therapy (FRT). To overcome the plateau in treatment advancement for DIPG, a novel, multi-modal approach to therapy is proposed that capitalizes on the al- ready proven potential of FRT for prognostic improvement and addresses two major issues associated with current clinical trials for DIPG. First, systemically-delivered drug penetration into DIPG tumors is severely limited by the highly-protective blood brain barrier (BBB). Second, many systemic therapies have been tested in DIPG by extrapolation from adult high grade glioma trials, without clear rationale for the translation of these therapies between two genetically distinct groups of tumors. To simultaneously overcome these issues, this project proposes to use DIPG-validated radiosensitizing agents - which will enhance the effects of FRT on DIPG cells - combined with a convection enhanced delivery (CED) system, which will bypass the BBB and al- low delivery of therapeutics directly to the tumor. Radiosensitizers will be encapsulated in polymeric nanoparticles (NP), which will slowly degrade after delivery into the tumor. This slow degradation provides sustained levels of drug in the tumor which allow effective radiosensitization during both the administration of FRT and the post-FRT recovery period of up to two weeks. This project is based on the hypothesis that the combination of FRT with CED of radiosensitizer-loaded NPs will inhibit DNA repair following FRT-induced dsDNA breaks, thus decreasing tumor recurrence and ultimately increasing overall patient survival. To test this hypothesis the project is divided into the three specific aims. The first aim focuses on the fabrication and testing of radiosensitizer-loaded NP in cell culture models for their effects o cellular DNA repair and survival following dsDNA breaks. The second aim focuses on CED of these NPs to rodent models of intracranial tumors in order to optimize their ability to homogeneously penetrate and be retained within the tumor. Finally, the third aim focuses on testing and optimizing the therapeutic efficacy of this approach by combining radiosensitizer-loaded NPs - optimized in aims 1 and 2 for inhibition of DNA repair and homogenous distribution and retention in intracranial tumors - with FRT in rodent models of DIPG. Completion of these proposed aims will demonstrate the feasibility of a new multi-modal approach to treatment of a devastating pediatric disease that has not seen prognostic improvement over the past 30 years. Additionally, this project will establish a precedent for the novel combination of CED delivery of radiosensitizer-loaded NPs for sustained radiosensitization during FRT that can be applied to other tumors of the brain and spine.